遗传学英文课件：Treatment of Genetic Disease

1、Learning Objectives,Conventional managements Surgery Internal medicine 2. Gene therapy,Treatment of Genetic Disease by Metabolic Manipulation,Wilson disease: Cu toxicity,Characteristics ofWilson Disease (AR),Liver disease recurrent jaundice, simple acute self-limited hepatitis-like illness, autoimmu

2、ne-type hepatitis, fulminant hepatic failure, or chronic liver disease. Neurologic presentations movement disorders (tremors, poor coordination, loss of fine-motor control, chorea, choreoathetosis) or rigid dystonia (mask-like facies, rigidity, gait disturbance, pseudobulbar involvement). Psychiatri

3、c disturbance depression, neurotic behaviors, disorganization of personality, and, occasionally, intellectual deterioration. Kayser-Fleischer rings: copper deposition in Descemets membrane of the cornea and reflect a high degree of copper storage in the body. Mild or acute hemolysis.,Wilson disease:

4、 Penicillamine therapy Before/After,Gene therapy,The medical procedure involves either replacing, manipulating, or supplementing nonfunctional genes with healthy genes.,In vivo and ex vivo Gene Therapy,Introduce a gene,Recover the Activity of an Enzyme,Recover the Activity of an Enzyme 287:1751.,Wha

5、t factors have kept GRx from becoming an effective treatment for genetic disease?,Short-lived nature of gene therapy Immune response Problems with viral vectors Multigene disorders.,Long Way to Go ,Colour blindness corrected by gene therapy,Nature, Vol. 461, No. 7261, September 16, 2009,The monkeys

6、were trained to touch a screen when they saw coloured patches - the standard Cambridge Colour Test,All male squirrel monkeys (Saimiri sciureus), which naturally see the world in just two tones,Dalton, a squirrel monkey treated with gene therapy, enjoys his new colour sense .Neitz Laboratory,Lebers C

7、ongenital Amaurosis (LCA),Autosomal recessive Early onset retinal degeneration blindness, abnormal eye movements in infancy & early childhood No treatment Many cases of LCA are caused by mutations in RPE65,(Patient #3 in the CHOP-Penn Study),LCA-RPE65 Normal,Bennett 6/08,1993,2007,2006,2005,2004,200

8、2,2001,2000,2003,1999,1998,1997,What it takes for The Foundation to help bring a treatment to the clinic,Example: RPE65 Gene Therapy for LCA (Lancelot Trial),discover RPE65 gene,link RPE65 gene to LCA,AAV GT vector production,Vector improvement: test in mice, dogs,choose AAV2 for human trial,large s

9、cale vector production,RPE65 is found to be retinyl ester binding protein,Create RPE65 Knockout mouse model,Discover RPE65 natural mutation in briard dog,treat Lancelot in 1 eye,publish Lancelot findings,treated over 50 dogs: all with improved vision,toxicity, biodistribution studies,Pre-IND with FD

10、A/CBER,Jacobson: Orphan drug IND application filed,Jacobson RAC for adults,High RAC for kids,Patient screening (phenotype, genotype),Jacobson: FDA release Phase I hold,Jacobson: await IRB approval,High will apply for FDA, IRB,Begin Phase I Clinical Trial,FFB has supported this project from the outse

11、t, and is still an active supporter,Foundation Fighting Blindness Visions 2008 Washington, DC August 10, 2008,Vision Recovery in Individuals with Congenital Blindness after Retinal Gene Therapy,Jean Bennett, M.D., Ph.D. On behalf of the CHOP-UPenn-TIGEM-SUN Team,A collaboration with: Seconda Univers

12、it degli Studi di Napoli,What are the Patients Reactions?,Can I have my other eye injected? They are happy with the results.,Bennett 6/08,Leber Congenital Amaurosis (LCA),Severe retina dystrophy, in the first year of life. Visual function is usually poor and often accompanied by nystagmus, sluggish

13、or near-absent pupillary responses, photophobia, high hyperopia, and keratoconus. Autosomal recessive 17 genes currently known for LCA: GUCY2D (locus name: LCA1), RPE65 (LCA2), SPATA7 (LCA3), AIPL1 (LCA4), LCA5 (LCA5), RPGRIP1 (LCA6), CRX (LCA7), CRB1 (LCA8), CEP290 (LCA10), IMPDH1 (LCA11), RD3 (LCA

14、12), and RDH12 (LCA13), account for, about 70% of all LCA.,Hunting for New LCA Gene,Nicotinamide Mononucleotide Adenylyltransferase 1, NMNAT1,maps to 1p36.22, near the previously mapped LCA9. not previously been linked to LCA but is associated with axonal degeneration. HomozygousNmnat1 knockout mice

15、 do not survive to birth, indicating the function of Nmnat1 is essential in mice. 4 coding exons, small 279-residue protein that has an important role in NAD+ biosynthesis, catalyzing the formation of NAD+ from nicotinamide mononucleotide (NMN) and ATP.,(Falk, et al Nat Genet, 2012),Mutations identi

16、fied in NMNAT1,Mutations identified in the NMNAT1 gene of LCA Patients,3-D Structure of Mutations identified in the NMNAT1 gene of LCA Patients,New Hope,Stem CellC Rx,Stem CellGRx,Restoring vision with stem cells,A British man, the first in Europe to take part in a stem cell trial for a rare and dev

17、astating eye disease,Marcus Hilton, 34 Stargardts macular dystrophy (SMD) 2012-1-20, Receive 50,000 retinal pigment epithelial (RPE) cells derived from human embryonic stem cells injected during a 90-minute operation at Moorfields Eye Hospital in London,Stargardts Macular Dystrophy,The most common form of inherited juvenile macular degeneration that causes progressive vision loss usually to the point o